Beyond apoptosis: Exploring necroptosis, ferroptosis, and pyroptosis in sevoflurane- and isoflurane-associated PNDs

Abstract

Perioperative neurocognitive disorders (PNDs) are common postoperative complications, particularly in elderly patients undergoing general anesthesia. While sevoflurane and isoflurane are widely used inhalational anesthetics, their association with PNDs requires deeper mechanistic investigation. Although apoptosis was traditionally considered the primary mechanism, recent evidence implicates non-apoptotic programmed cell death (PCD) pathways-necroptosis, ferroptosis, and pyroptosis-in PND pathogenesis. These pathways amplify neuroinflammation and neuronal damage through distinct molecular mechanisms. This review synthesizes current understanding of these PCD pathways in inhalational anesthetic-induced neurotoxicity, evaluating their molecular signatures and interactions. We identify critical knowledge gaps and propose research directions focusing on pathway dominance, crosstalk, and multi-target therapeutic strategies. These insights advance PND pathophysiology understanding and inform novel treatment development.